ABSTRACT/SUMMARY Increasing understanding of the heterogeneity of breast cancer is leading to tailored therapies that hold promise for improving outcomes. The I-SPY2 TRIAL is a phase II, multicenter trial designed to test new treatment strategies for breast cancer and to quickly identify promising candidate therapies for subsequent phase III testing. MRI is used in I-SPY2 to monitor primary tumor response to neoadjuvant chemotherapy (NAC) and to provide prognostic information. The overall objective of the Program Project is to develop and implement an adaptive strategy to redirect NAC based on early treatment response indicators. The goal is to improve outcomes for women with stage 2/3 breast cancer who remain at highest risk for recurrence, and minimize chemo-toxicities in women at lowest risk. As a component of the Program Project, Project 2 will systematically develop integrated imaging predictive models that can be used to decide mid-treatment modification of NAC based on individual response. These models will be initially developed using the extensive existing DCE-MRI database in I-SPY2, and augmented over time with imaging data emerging from more recent addition of DWI and PET. Information from Project 3 about molecular determinants of treatment resistance will be used to further refine the prognostic ability of imaging models. We will look more closely at the relationship between measures of residual disease by MRI and histopathology, in order to further improve MRI's ability to serve as a non-invasive surrogate of residual disease. Lastly, recognizing that PET imaging may provide additional insight into drug mechanism of action in combination with MRI, we will begin to expand the use of PET through a pilot study performed at a sub-set of sites using dedicated breast PET (dbPET) scanners. Project 2 leverages the substantial existing data set from the multi-agent I-SPY2 clinical trial, consisting of serial MRIs linked to outcomes for over 1000 subjects receiving experimental treatments. We expect the successful completion of aims to afford more powerful non-invasive imaging methods that will facilitate the personalization of NAC and improve overall outcomes for patients with breast cancer.